title: Mate pair sequencing for the detection of chromosomal aberrations in patients with intellectual disability and congenital malformations.
abstract: Recently, microarrays have replaced karyotyping as a first tier test in patients with idiopathic intellectual disability and/or multiple congenital abnormalities (ID/MCA) in many laboratories. Although in about 14-18% of such patients, DNA copy-number variants (CNVs) with clinical significance can be detected, microarrays have the disadvantage of missing balanced rearrangements, as well as providing no information about the genomic architecture of structural variants (SVs) like duplications and complex rearrangements. Such information could possibly lead to a better interpretation of the clinical significance of the SV. In this study, the clinical use of mate pair next-generation sequencing was evaluated for the detection and further characterization of structural variants within the genomes of 50 ID/MCA patients. Thirty of these patients carried a chromosomal aberration that was previously detected by array CGH or karyotyping and suspected to be pathogenic. In the remaining 20 patients no causal SVs were found and only benign aberrations were detected by conventional techniques. Combined cluster and coverage analysis of the mate pair data allowed precise breakpoint detection and further refinement of previously identified balanced and (complex) unbalanced aberrations, pinpointing the causal gene for some patients. We conclude that mate pair sequencing is a powerful technology that can provide rapid and unequivocal characterization of unbalanced and balanced SVs in patient genomes and can be essential for the clinical interpretation of some SVs.
authors.affiliation: Center for Medical Genetics, Ghent University, Ghent, Belgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: Vergult
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Ellen
authors.initials: E
authors.lastname: Van Binsbergen
authors.affiliation: Center for Medical Genetics, Ghent University, Ghent, Belgium.
authors.forename: Tom
authors.initials: T
authors.lastname: Sante
authors.affiliation: Center for Medical Genetics, Ghent University, Ghent, Belgium.
authors.forename: Silke
authors.initials: S
authors.lastname: Nowak
authors.affiliation: Center for Medical Genetics, Ghent University, Ghent, Belgium.
authors.forename: Olivier
authors.initials: O
authors.lastname: Vanakker
authors.affiliation: Center for Medical Genetics, Ghent University, Ghent, Belgium.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Claes
authors.affiliation: Center for Medical Genetics, Ghent University, Ghent, Belgium.
authors.forename: Bruce
authors.initials: B
authors.lastname: Poppe
authors.affiliation: Department for Medical Genetics, University Hospital of Antwerp, Antwerp, Belgium.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Van der Aa
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Markus J
authors.initials: MJ
authors.lastname: van Roosmalen
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Karen
authors.initials: K
authors.lastname: Duran
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Masoumeh
authors.initials: M
authors.lastname: Tavakoli-Yaraki
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Marielle
authors.initials: M
authors.lastname: Swinkels
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Marie-José
authors.initials: MJ
authors.lastname: van den Boogaard
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Mieke
authors.identifier: 0000000275190246
authors.initials: M
authors.lastname: van Haelst
authors.affiliation: Heilig Hart Ziekenhuis, Roeselare, Belgium.
authors.forename: Filip
authors.initials: F
authors.lastname: Roelens
authors.affiliation: Center for Medical Genetics, Ghent University, Ghent, Belgium.
authors.forename: Frank
authors.initials: F
authors.lastname: Speleman
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Edwin
authors.identifier: 0000000204009542
authors.initials: E
authors.lastname: Cuppen
authors.affiliation: 1] Center for Medical Genetics, Ghent University, Ghent, Belgium [2] Department for Medical Genetics, University Hospital of Antwerp, Antwerp, Belgium.
authors.forename: Geert
authors.initials: G
authors.lastname: Mortier
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Wigard P
authors.initials: WP
authors.lastname: Kloosterman
authors.affiliation: Center for Medical Genetics, Ghent University, Ghent, Belgium.
authors.forename: Björn
authors.initials: B
authors.lastname: Menten
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics*; D002869:Chromosome Aberrations; D002871:Chromosome Banding; D058674:Chromosome Duplication; D002887:Chromosomes, Human, Pair 18; D002891:Chromosomes, Human, Pair 21; D055028:Comparative Genomic Hybridization; D019295:Computational Biology; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D059785:Karyotype; D008297:Male; D011995:Recombination, Genetic